Sotorasib Shows Impressive 2-Year OS Rate in KRAS G12C+ NSCLC


Sotorasib demonstrated a 32.5% overall survival rate at 2 years in patients with KRAS G12C mutation non-small cell lung cancer, according to longer follow-up data from the phase 1 trial /2 CodeBreaK 100.

Sotorasib (Lumakras) demonstrated an overall survival (OS) rate of 32.5% (95% CI, 25.0% to 40.2%) at 2 years in patients with kras G12C mutant non-small cell lung cancer (NSCLC), according to longer follow-up data from the Phase 1/2 CodeBreaK 100 trial (NCT03600883) that were presented at the 2022 AACR Annual Meeting.1.2

Additional results showed that the overall response rate (ORR) achieved with sotorasib was 40.7% (95% CI, 33.3% to 48.4%) and the disease control rate (DCR ) was 83.7% (95% CI, 77.3% to 88.9%). . Additionally, the median duration of response (DOR) was 12.3 months (95% CI, 7.1-15.0) and 50.6% (95% CI, 37.4%-62.4 %) of responders had been in response for at least 12 months.

Median progression-free survival (PFS) was 6.3 months (95% CI, 5.3-8.2) and median OS was 12.5 months (95% CI, 10.0-17, 8). At 1 year, the OS rate was 50.8% (95% CI, 42.8%-58.2%).

“In this longest follow-up of patients on any KRAS G12C inhibitor, sotorasib has demonstrated highly significant and durable efficacy, as well as a safety profile [that was] consistent with what had been [previously] reported,” said Grace K. Dy, MD, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center, in a press conference at the meeting. “We also reported a 2 year old [OS rate] of [approximately] 33% in [patients with] pretreated kras G12C-mutated NSCLC, which compares favorably to what we would expect with historical therapy using docetaxel in this setting.

In May 2021, the FDA approved Sotorasibfor the treatment of locally advanced or metastatic patients kras G12C mutant NSCLC who have not received prior treatment. The regulatory decision was based on earlier results from the CodeBreaK 100 trial.3

The pooled Phase 1/2 CodeBreak 100 trial enrolled a total of 174 patients with locally advanced or metastatic disease. kras Mutant G12C solid tumors. Patients had received at least 1 prior systemic therapy or were ineligible or intolerant to treatment. Those with stable brain metastases were allowed.

In the trial, study participants received oral sotorasib at the FDA-approved dose, which was 960 mg once daily, until disease progression. Radiographic examinations were performed every 6 weeks until week 48, then once every 12 weeks thereafter.

In phase 1 research (n=48), the primary endpoint was safety and tolerability; primary secondary endpoints were pharmacokinetics, ORR, DOR, PFS, and duration of disease stabilization. In phase 2 of the trial (n=126), the primary outcome measure was ORR according to RECIST v1.1 criteria by blinded independent central review. Primary secondary endpoints were DOR, DCR, PFS, OS, time to response, and safety.

For the updated analysis, the data cut-off date was February 22, 2022. The median duration of follow-up for OS was 24.9 months.

In the updated analysis, investigators analyzed data from 174 patients who were treated with sotorasib in combined phases 1 and 2 of CodeBreaK 100; these patients received the FDA-approved dose of sotorasib 960 mg daily. Notably, 82.8% of patients had previously received both platinum-based chemotherapy and anti-PD-1/PD-L1 therapy.

Additional results showed that the clinical activity of sotorasib was observed independent of PD-L1 expression and was observed in individuals with low PD-L1 levels. “Our results also support studies that investigate incorporating sotorasib earlier in treatment to improve patient outcomes. [with] NSCLC who are less likely to benefit from immunotherapy,” Dy said in a press release.

Further analyzes were conducted on tumor and plasma samples to identify biomarker profiles linked to sustained clinical benefit. These studies showed that a prolonged clinical benefit was observed regardless of the weight of tumor mutations, the expression of PD-L1 and STK11 co-mutation status.

In patients with PD-L1 expression less than 1% (n=31), PFS benefit with sotorasib lasted at least 12 months in 51.6% of patients; in those with PD-L1 expression between 1% and 49% (n=21), this rate was 28.6%. In patients who had PD-L1 expression of at least 50% (n=4), 25.0% of patients had a PFS benefit of at least 12 months.

In patients with STK11-mutant/KEAP1 wild-type (n = 13), long-term PFS benefit was at least 12 months in 46.2%; this was the case for 45.5% of people STK11 wild type/KEAP1 wild-type disease (n = 33). In those with STK11-mutant/KEAP1– mutant disease (n = 12), a PFS benefit of at least 12 months was felt by 16.7% of patients; this was also the case for 14.3% of people STK11 wild type/KEAP1– mutant disease (n = 7).

“Longer-term follow-up data is important to better define the safety and efficacy of sotorasib, as it is the first KRAS G12C inhibitor therapy to be approved for this patient population,” Dy added in the press release. “For this particular analysis, we also sought to determine if there are any potential biomarkers that can identify patients who will derive long-term benefit from sotorasib treatment.”

No new safety issues were observed with long-term treatment with sotorasib. Grade 3/4 treatment-related adverse events (ETRA) occurred in 21% of patients, and 1 patient experienced a new grade 3 ETRA of haemolytic anemia after 1 year. Notably, no TRAE-related deaths occurred, and no TRAE led to discontinuation after 1 year of treatment.

“[Overall], most toxicities were grade 1/2 in severity; the main ISs were [gastrointestinal] in nature [with] nausea, diarrhea, [liver function test] abnormal, and 22% of patients required dose modifications or dose interruptions; around 6% required discontinuation of the dose,” Ly said in the presentation, adding that around a quarter of patients remain on treatment after 1 year.

CodeBreaK 100 is a single-arm, non-randomized trial, which the investigators noted as a limitation. The global randomized Phase 3 CodeBreaK 200 study (NCT04303780) is ongoing and includes a comparator arm of docetaxel in patients with kras G12C mutant NSCLC.

“We look forward to the results of the Phase 3 study, which will likely be available later this year, and hope they confirm our CodeBreaK 100 findings,” Dy said in the press release.


  1. Dy GK, Govindan R, Velcheti V, et al. Long-term results with sotorasib in pretreated KRASp.G12C mutated NSCLC: 2-year analysis of CodeBreaK100. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022, New Orleans, LA. Summary CT008.
  2. The KRAS G12C inhibitor sotorasib may provide long-term clinical benefit in patients with non-small cell lung cancer. Press release. American Association for Cancer Research; April 10, 2022. Accessed April 10, 2022.
  3. FDA approves first targeted therapy for lung cancer mutation previously considered drug-resistant. Press release. FDA; May 28, 2021. Accessed April 10, 2022.


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